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Objective: Historically, epilepsy has been the most frequently presenting feature of tuberous sclerosis complex (TSC). Advances in TSC health care have occurred over the past decade; thus, we studied whether TSC epilepsy outcomes have changed. Method: A retrospective chart review was undertaken for all children with TSC in Queensland, Australia. Epilepsy outcome and TSC diagnosis data were extracted, and data were compared between children born before 2012 with those born in or after 2012. Results: In this retrospective cohort, TSC diagnosis in children born in or after 2012 is now predominantly antenatal (51%, p <.05). Most patients with epilepsy are now known to have TSC before they develop epilepsy. Despite earlier TSC diagnosis, the frequency of epilepsy (85%) has not changed (p =.92), but diagnosis trends toward an earlier age (median = 3 months for patients born in or after 2012 vs. 5.5 months for those born before 2012, p =.23). Most (95%) patients had focal seizures as their initial clinical seizure type; it was rare (5%) for epileptic spasms (ES) to be the initial seizure type. The frequency of ES was lower in patients born in or after 2012 (36% vs. 50%, p =.27). Infantile (<24 months) onset ES was not associated with worse epilepsy outcome. Late onset ES was seen in 14%, and these patients had a lower rate of epilepsy remission. Lennox–Gastaut syndrome was seen in 7%. Febrile/illness‐related status epilepticus occurred in 12% of patients, between 1 and 4 years of age. Despite many (78%) patients having multiple daily seizures at maximal seizure frequency, and 74% meeting criteria for treatment‐refractory epilepsy, most patients achieved epilepsy remission (66%), either with epilepsy surgery (47%) or with age (53%). At the time of inclusion in this study, only 21% of patients had uncontrolled frequent (daily to 3 monthly) seizures and 14% had uncontrolled infrequent (3 monthly to <2 yearly) seizures. Significance: This study provides updated information that informs the counseling of parents of newly diagnosed pediatric TSC patients. [ABSTRACT FROM AUTHOR]

Limited guidelines exist regarding osteoporosis prevention in the general population. Despite being a subject of controversy, the majority of research suggests that decreased vitamin D levels correlate with increased bone turnover, that is, an important risk factor for osteoporosis development. In most guidelines, daily vitamin D supplementation is recommended. In persons with epilepsy (PWE), the situation is more complex, as other factors can increase the chance of being vitamin D deficient. Currently, there are no internationally accepted guidelines regarding monitoring bone health in PWE. Our aim was to review the existing evidence in PWE on: (1) risk factors for vitamin D deficiency, (2) the identification of higher risk groups, and (3) the optimal ways to monitor bone health. Our narrative review shows that: (1) anti‐seizure medication (ASM) use, especially enzyme‐inducing ASM (EIASM) and valproic acid, is identified as an important risk factor for impaired bone health (e.g., increased risk for osteoporosis/fractures and/or vitamin D deficiency); (2) higher risk groups within the PWE population are present: intellectual or physical disability, institutionalized patients, puberty, early onset epilepsy and developmental epileptic encephalopathies, postmenopausal women, and use of multiple ASM/concomitant drugs (e.g. corticosteroids); and (3) a monitoring scheme can be suggested including laboratory tests, bone density measurements, managing of risk factors, and/or vitamin D supplementation. Overall, regular vitamin D measurement in PWE is a cost‐effective and practical method for monitoring vitamin D deficiency, whereas in high‐risk patients the combination of vitamin D measurement and bone densitometry is recommended. There is not enough evidence to advocate continuous vitamin D supplementation in all PWE. Children with epilepsy should receive the recommended daily intake of vitamin D for age and additional monitoring and supplementation if at higher risk of deficiency. There is a need for prospective trials exploring the potential benefit of vitamin D supplementation in PWE. [ABSTRACT FROM AUTHOR]

Epilepsies are a diverse group of disorders which differ regarding prognosis for seizure control and associated comorbidities. Accurate classification is critical to choose the highest yield investigations and best therapeutic options and to provide the most accurate prognoses regarding the expected degree of seizure control, possible remission, and risk of associated comorbidities to patients and their families. This article reviews the recent updates in epilepsy classification to illustrate how accurate classification impacts care for persons with epilepsy. The authors discuss the ILAE 2017 Classification of the Epilepsies along with the modification of the classification for neonatal seizures and epilepsies. They also discuss the ILAE position papers on Epilepsy syndromes in neonates and infants and children of variable age and the Idiopathic Generalized Epilepsies. Accurate epilepsy classification allows selection of the highest yield investigations, choice of optimal therapies, and accurate prognostication of seizures (likelihood of response to antiseizure treatments and likelihood of remission with age), as well as comorbidities (likelihood, type, and severity). As we move into the era of disease modifying therapy, early accurate identification of underlying causes with timely introduction of specific treatments will be crucial to lessen the severity of epilepsy, with improved seizure control and attenuation of associated comorbidities. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. Methods: This multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2–18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6‐week baseline period were randomized to placebo, fenfluramine.2 mg/kg/day, or fenfluramine.7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine.7 mg/kg/day versus patients given placebo. Results: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine.7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p <.0001). Following fenfluramine.7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p <.0001). The median longest seizure‐free interval was 30 days in the fenfluramine.7 mg/kg/day group compared with 10 days in the placebo group (p <.0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. Significance: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome. [ABSTRACT FROM AUTHOR]

Objective: Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to market authorization (MA). For treatment of – especially young – children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to "off‐label" use of ASMs. Even though "off‐label" ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if "on‐label" ASM, in mono‐ or polytherapy, fails to achieve adequate seizure control. Methods: The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first‐ and second‐line treatment preferences but also to illustrate the use of "off‐label" drugs in childhood epilepsies. Results: Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed "off‐label" in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap. Significance: We report the relatively common use of "off‐label" prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence‐based guidelines. [ABSTRACT FROM AUTHOR]

Objective: The objectives of this study were to assess the accuracy of parental seizure detection in infants with antenatally diagnosed tuberous sclerosis complex (TSC), and to document the total seizure burden (clinical and subclinical) in those patients who met criteria for prolonged electroencephalography (EEG) recording. Methods: Consecutive infants at a single institution with antenatally diagnosed TSC who met criteria for prolonged video‐EEG (vEEG) were recruited to this study. The vEEG data were reviewed and when a seizure was identified on EEG, the video and audio recording was assessed for evidence of clinical seizure and, if present, whether there was evidence of parent seizure identification. Results: Nine infants were enrolled, for whom 674 focal seizures were identified in eight of nine patients across 24 prolonged vEEG recordings, with vEEG total duration of 634 h 49 min (average seizure frequency of 1 focal seizure/h). Only 220 of 674 (32.6%) were clinical seizures, 395 of 674 (58.6%) were subclinical seizures, and 59 of 674 seizures could not be classified. Only 63 of 220 clinical seizures (28.6%) were identified by parents, with 157 of 220 (71.4%) not identified. Thirty clusters of epileptic spasms were detected in one patient. At least one clinical epileptic spasm occurred in 2 of 30 clusters (6.7%), 24 of 30 clusters of epileptic spasms (80%) were electrographic only, and classification was uncertain for 4 of 30 clusters (13.3%). No clinical epileptic spasms were detected by parents. Clinical seizure frequency was significantly underestimated by parents for all patients. Significance: This study demonstrates that in infants with TSC who met criteria for prolonged vEEG, (1) parents significantly under recognize total clinical seizure count, (2) parents fail to identify epileptic spasms, and (3) seizure frequency is high. This highlights that epilepsy treatment decisions should not be based solely on parental clinical seizure identification. Prolonged vEEG monitoring may have an important role in the routine epilepsy care of infants with TSC, as demonstrating undetected high clinical seizure frequency may allow improved epilepsy management decisions. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to evaluate the long‐term safety and effectiveness of fenfluramine in patients with Lennox–Gastaut syndrome (LGS). Methods: Eligible patients with LGS who completed a 14‐week phase 3 randomized clinical trial enrolled in an open‐label extension (OLE; NCT03355209). All patients were initially started on.2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3‐month intervals. The protocol‐specified treatment duration was 12 months, but COVID‐19‐related delays resulted in 142 patients completing their final visit after 12 months. Results: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2–4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was −28.6% over the entire OLE (n = 241) and −50.5% at Month 15 (n = 142, p <.0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was −45.9% (n = 192, p =.0038). Generalized tonic–clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p <.0001, n = 106) and 35.8% (p <.0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%–44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%–41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment‐emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. Significance: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long‐term. Fenfluramine may provide an important long‐term treatment option for LGS. [ABSTRACT FROM AUTHOR]

Introduction: Peri-insular hemispherotomy (PIH) is a hemispheric separation technique under the broader hemispherotomy group, a surgical treatment for patients with intractable epilepsy. Hemispherotomy techniques such as the PIH, vertical parasagittal hemispherotomy (VPH), and modified-lateral hemispherotomy are commonly assessed together, despite significant differences in anatomical approach and patient selection. We aim to describe patient selection, outcomes, and complications of PIH in its own right. Methods: A systematic review of the literature, in accordance with the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was conducted, with searches of the PubMed and Embase databases. A local series including patients receiving PIH and followed up at the Queensland Children's Hospital between 2014 and 2020 was included. Results: Systematic review of the literature identified 393 patients from 13 eligible studies. Engel class 1 outcomes occurred in 82.4% of patients, while 8.6% developed post-operative hydrocephalus. Hydrocephalus was most common in the youngest patient cohorts. Developmental pathology was present in 114 (40.8%) patients, who had fewer Engel 1 outcomes compared to those with acquired pathology (69.1% vs. 83.7%, p = 0.0167). The local series included 13 patients, 11/13 (84.6%) had Engel class 1 seizure outcomes. Post-operative hydrocephalus occurred in 2 patients (15.4%), and 10/13 (76.9%) patients had worsened neurological deficit. Conclusion: PIH delivers Engel 1 outcomes for over 4 in 5 patients selected for this procedure, greater than described in combined hemispherectomy analyses. It is an effective technique in patients with developmental and acquired pathologies, despite general preference of VPH in this patient group. Finally, very young patients may have significant seizure and cognitive benefits from PIH; however, hydrocephalus is most common in this group warranting careful risk-benefit assessment. This review delivers a dedicated PIH outcomes analysis to inform clinical and patient decision-making. [ABSTRACT FROM AUTHOR]

Objective: Paediatric status epilepticus (SE) has potential for long‐term sequelae. Existing data demonstrate delays to aspects of care. The objective of the present study was to examine the feasibility of collecting data on children with paediatric SE and describe current management strategies in pre‐hospital and in‐hospital settings. Methods: A pilot, prospective, observational cohort study of children 4 weeks to 16 years of age with SE, in four EDs in Australia. Clinical details including medications administered, duration of seizure and short‐term outcomes were collected. Follow up occurred by telephone at 1 month. Results: We enrolled 167 children with SE. Mean age was 5.4 years (standard deviation [SD] 4.1), and 81 (49%) male. Median seizure duration was 10 min (interquartile range 7–30). Midazolam was the first medication administered in 87/100 (87%) instances, mean dose of 0.21 mg/kg (SD 0.13). The dose of midazolam was adequate in 30 (35%), high (>0.2 mg/kg) in 44 (51%) and low (<0.1 mg/kg) in 13 (15%). For second‐line agents, levetiracetam was administered on 33/55 (60%) occasions, whereas phenytoin and phenobarbitone were administered on 11/55 (20%) occasions each. Mean dose of levetiracetam was 26.4 mg/kg (SD 13.5). One hundred and four (62%) patients were admitted to hospital, with 13 (8%) admitted to ICU and seven (4%) intubated. Conclusion: In children presenting with SE in Australia medical management differed from previous reports, with midazolam as the preferred benzodiazepine, and levetiracetam replacing phenytoin as the preferred second‐line agent. This pilot study indicates the feasibility of a paediatric SE registry and its utility to understand and optimise practice. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients' serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients. [ABSTRACT FROM AUTHOR]

Background. The genomic era has led to enormous progress in clinical care and a multi-disciplinary team (MDT) approach is imperative for integration of genomics into epilepsy patient care. Methods. The MDT approach involved patient selection, genomic testing choice, variant discussions and return of results. Genomics analysis included cytogenomic testing and whole exome sequencing (WES). Neurologist surveys were undertaken at baseline and after genomic testing to determine if genomic diagnoses would alter their management, and if there was a change in confidence in genomic testing and neurologist perceptions of the MDT approach. Results. The total diagnostic yield from all genomic testing was 17% (11/66), with four diagnoses from cytogenomic analyses. All chromosomal microarray (CMA) diagnoses were in patients seen by adult neurologists. Diagnostic yield for WES was 11% (7/62). The most common gene with pathogenic variants was DCX, reported in three patients, of which two were mosaic. The genomic diagnosis impacted management in 82% (9/11). There was increased confidence with integrating genomics into clinical care (Pearson chi square = 83, p = 0.004) and qualitative comments were highly supportive of the MDT approach. Conclusions. We demonstrated diagnostic yield from genomic testing, and the impact on management in a cohort with drug-resistant epilepsy. The MDT approach increased confidence in genomic testing and neurologists valued the input from this approach. The utility of CMA was demonstrated in epilepsy patients seen by adult neurologists as was the importance of considering mosaicism for previously undiagnosed patients. [ABSTRACT FROM AUTHOR]

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017–2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients. [ABSTRACT FROM AUTHOR]

The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene‐related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self‐limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology‐specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology‐defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource‐limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available. [ABSTRACT FROM AUTHOR]

Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as "a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)." The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age‐dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers. [ABSTRACT FROM AUTHOR]

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic–clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017–2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic‐clonic and myoclonic‐tonic‐clonic seizures, with 2.5–5.5 Hz generalized spike‐wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

The 2017 International League Against Epilepsy classification has defined a three‐tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self‐limited focal epilepsies, comprising four syndromes: self‐limited epilepsy with centrotemporal spikes, self‐limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic–atonic seizures, Lennox–Gastaut syndrome, developmental and/or epileptic encephalopathy with spike‐and‐wave activation in sleep, hemiconvulsion–hemiplegia–epilepsy syndrome, and febrile infection‐related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations. [ABSTRACT FROM AUTHOR]

Summary: Objective: To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED‐EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC). Methods: Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy – Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED‐EEG were studied in relation to clinical outcome. Epilepsy‐related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]). Results: Eighty‐three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14–54). Seventy‐nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23–111). Patients with a pathogenic TSC2 variant were significantly younger (P‐value.009) at first ED‐EEG and more frequently had multifocal IED (P‐value.042) than patients with a pathogenic TSC1 variant. A younger age at first ED‐EEG was significantly associated with lower cognitive (P‐value.010), language (P‐value.001), and motor (P‐value.013) developmental quotients at 24 months. In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED‐EEG was predictive of earlier seizure onset (P‐value.030). Earlier recording of epileptiform discharges (P‐value.019), especially when multifocal (P‐value.026) was associated with higher risk of drug‐resistant epilepsy. In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED‐EEG, preventive treatment delayed the onset of seizures significantly (P‐value <.001). Significance: Early EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin. [ABSTRACT FROM AUTHOR]

Objective: Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants. Methods: In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open‐label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure. Results: In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty‐seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223–535) vs 124 days (95% CI = 33–149); OLT: 426 days (95% CI = 258–628) vs 106 days (95% CI = 11–149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug‐resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted. Interpretation: Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304–314 [ABSTRACT FROM AUTHOR]

Ring chromosomes occur when the ends of normally rod‐shaped chromosomes fuse. In ring chromosome 20 (ring 20), intellectual disability and epilepsy are usually present, even if there is no deleted coding material; the mechanism by which individuals with complete ring chromosomes develop seizures and other phenotypic abnormalities is not understood. We investigated altered gene transcription as a contributing factor by performing RNA‐sequencing (RNA‐seq) analysis on blood from seven patients with ring 20, and 11 first‐degree relatives (all parents). Geographic analysis did not identify altered expression in peritelomeric or other specific chromosome 20 regions. RNA‐seq analysis revealed 97 genes potentially differentially expressed in ring 20 patients. These included one epilepsy gene, NPRL3, but this finding was not confirmed on reverse transcription Droplet Digital polymerase chain reaction analysis. Molecular studies of structural chromosomal anomalies such as ring chromosome are challenging and often difficult to interpret because many patients are mosaic, and there may be genome‐wide chromosomal instability affecting gene expression. Our findings nevertheless suggest that peritelomeric altered transcription is not the likely pathogenic mechanism in ring 20. Underlying genetic mechanisms are likely complex and may involve differential expression of many genes, the majority of which may not be located on chromosome 20. [ABSTRACT FROM AUTHOR]

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with a high risk of early-onset epilepsy and a high prevalence of neurodevelopmental comorbidities, including intellectual disability and autism spectrum disorder (ASD). Therefore, TSC is an interesting disease model to investigate early biomarkers of neurodevelopmental comorbidities when interventions are favourable. We investigated whether early EEG characteristics can be used to predict neurodevelopment in infants with TSC. The first recorded EEG of 64 infants with TSC, enrolled in the international prospective EPISTOP trial (recorded at a median gestational age 42 4/7 weeks) was first visually assessed. EEG characteristics were correlated with ASD risk based on the ADOS-2 score, and cognitive, language, and motor developmental quotients (Bayley Scales of Infant and Toddler Development III) at the age of 24 months. Quantitative EEG analysis was used to validate the relationship between EEG background abnormalities and ASD risk. An abnormal first EEG (OR = 4.1, p -value = 0.027) and more specifically a dysmature EEG background (OR = 4.6, p -value = 0.017) was associated with a higher probability of ASD traits at the age of 24 months. This association between an early abnormal EEG and ASD risk remained significant in a multivariable model, adjusting for mutation and treatment (adjusted OR = 4.2, p -value = 0.029). A dysmature EEG background was also associated with lower cognitive (p -value = 0.029), language (p -value = 0.001), and motor (p -value = 0.017) developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80–150 mg/kg/day). Methods: Infants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule). Results: Eighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months. Interpretation: This study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years. [ABSTRACT FROM AUTHOR]

Purpose: Status epilepticus (SE) is a paediatric emergency with significant morbidity and mortality. Recommendations beyond first line care are not based on high quality evidence. Emergency physicians and neurologists are key stakeholders in managing this condition. A collaborative, widely consulted approach to identifying priorities can help direct limited research funds appropriately. The objectives of this study are to identify consensus research priorities in paediatric SE among experts and health consumers.Methods: A three-stage Delphi process was conducted. Paediatric Neurologists and Emergency Physicians in Australia and New Zealand participated. Round one asked participants to generate three research questions important for further research in paediatric status epilepticus. Responses were refined into unique individual questions. Rounds two and three required participants to rate questions on a seven point ordinal scale. Health consumers were invited to participate by providing up to three problem areas that could be addressed by research.Results: 54 experts and 76 health consumers participated in the process. Nine questions reached our definition of consensus "high priority", 21 questions achieved consensus "low priority" and seven questions did not achieve consensus. High priority areas included second line management including levetiracetam (efficacy, dose and timing), use of third line agents, induction of anaesthesia (timing and best agent), management of focal SE, and indicators of "subtle SE". Consumer priority areas included themes of treatment efficacy, aetiology, and community education.Conclusion: We identified nine priority research questions in paediatric SE, congruent with the health consumer theme of treatment efficacy. Future research efforts should be directed towards these priority areas. [ABSTRACT FROM AUTHOR]

Paediatric status epilepticus ( SE) is a medical emergency and a common critical condition confronting pre-hospital providers. Management in the pre-hospital environment is challenging but considered extremely important as a potentially modifiable factor on outcome. Recent data from multicentre clinical trials, quality observational studies and consensus documents have influenced management in this area, and is important to both pre-hospital providers and emergency physicians. The objective of this review was to: (i) present an overview of the available evidence relevant to pre-hospital care of paediatric SE; and (ii) assess the current pre-hospital practice guidelines in Australia and New Zealand. The review outlines current definitions and guidelines of SE management, regional variability in pre-hospital protocols within Australasia and aspects of pre-hospital care that could potentially be improved. Contemporary data is required to determine current practice in our setting. It is important that paediatric neurologists, emergency physicians and pre-hospital care providers are all engaged in future endeavours to improve clinical care and knowledge translation efforts for this patient group. [ABSTRACT FROM AUTHOR]

The article discusses development associated with paediatric neurology in Australia and New Zealand. It is noted that very significant technical changes which have revolutionised the medical industry to characterise and treat neurological conditions in children, and which have affected all aspects of neurological investigation and management.

Objective Methods Results Significance Previous retrospective studies have reported vigabatrin‐associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM‐related symptoms were reported in TSC infants.The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty‐nine age‐matched non‐TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid‐attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated.Prevalence of VABAM in VGB‐treated TSC patients was 35.5%. VABAM‐like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43–6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB‐treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM‐like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68–8.77).VABAM are common in VGB‐treated TSC infants; however, VABAM‐like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM‐like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well‐known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms. [ABSTRACT FROM AUTHOR]

Objective: To correlate fetal brain magnetic resonance imaging (MRI) findings with epilepsy characteristics and neurodevelopment at 2 years of age in children with tuberous sclerosis complex (TSC) to improve prenatal counseling.Study Design: This retrospective cohort study was performed in a collaboration between centers of the EPISTOP consortium. We included children with definite TSC, fetal MRIs, and available follow-up data at 2 years of age. A pediatric neuroradiologist masked to the patient's clinical characteristics evaluated all fetal MRIs. MRIs were categorized for each of the 10 brain lobes as score 0: no (sub)cortical lesions or doubt; score 1: a single small lesion; score 2: more than one small lesion or at least one large lesion (>5 mm). Neurologic manifestations were correlated to lesion sum scores.Results: Forty-one children were included. Median gestational age at MRI was 33.3 weeks; (sub)cortical lesions were detected in 97.6%. Mean lesion sum score was 4.5. At 2 years, 58.5% of patients had epilepsy and 22% had drug-resistant epilepsy. Cognitive, language, and motor development were delayed in 38%, 81%, and 50% of patients, respectively. Autism spectrum disorder (ASD) was diagnosed in 20.5%. Fetal MRI lesion sum scores were significantly associated with cognitive and motor development, and with ASD diagnosis, but not with epilepsy characteristics.Conclusions: Fetal cerebral lesion scores correlate with neurodevelopment and ASD at 2 years in children with TSC. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is highly prevalent in subjects with Tuberous Sclerosis Complex (TSC), but we are not still able to reliably predict which infants will develop ASD. This study aimed to identify the early clinical markers of ASD and/or developmental delay (DD) in infants with an early diagnosis of TSC. We prospectively evaluated 82 infants with TSC (6–24 months of age), using a detailed neuropsychological assessment (Bayley Scales of Infant Development—BSID, and Autism Diagnostic Observation Schedule—ADOS), in the context of the EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy—Tuberous SclerOsis ComPlex) project (NCT02098759). Normal cognitive developmental quotient at 12 months excluded subsequent ASD (negative predictive value 100%). The total score of ADOS at 12 months clearly differentiated children with a future diagnosis of ASD from children without (p = 0.012). Atypical socio-communication behaviors (p < 0.001) were more frequently observed than stereotyped/repetitive behaviors in children with ASD at 24 months. The combined use of BSID and ADOS can reliably identify infants with TSC with a higher risk for ASD at age 6–12 months, allowing for clinicians to target the earliest symptoms of abnormal neurodevelopment with tailored intervention strategies. [ABSTRACT FROM AUTHOR]